Fight Colorectal Cancer (Fight CRC) advocates for the research community to commit more resources to colorectal cancer (CRC) research, including potential breakthrough projects that lead to better outcomes in treatment and prevention. We know how vital research is to advance the path to a cure. 

Fight CRC is reaching out to our research community to get their perspective on the progress that has been made and where we still need to go. 

This month, we interviewed Scott Kopetz, MD, PhD. Dr. Kopetz is a professor and physician-scientist in the Department of Gastrointestinal (GI) Medical Oncology, Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center in Houston, Texas.

As a member of Fight CRC’s immunotherapy workgroup, he is a champion for immunotherapy research and clinical care.

Looking back from the beginning of your career until now, what progress has been made in advancing CRC treatments? 

When I started my career, cytotoxic agents like 5-FU, oxaliplatin, and irinotecan were our main treatment options, and there was a very limited understanding of the molecular subsets of CRC. We were just bringing in targeted therapies -- we had not even implemented KRAS testing, for example. It's been exciting to see over time the development of targeted therapies in an initially very unselected way and the recognition of molecular subtypes to identify patients who may benefit from existing therapies.

And more recently, the recognition of molecular subtypes that we can directly target, leading to therapies targeting mutations including KRAS, HER2, BRAF, and MSI high CRC. I think it is exciting to see the progress that we've made, but also daunting to recognize how long progress takes. There is a feeling that there are limited treatment options for stage IV patients and in the past 10 years, progress of therapies that improve or extend the lives of CRC patients has been extremely slow. But when viewed by the lens of a longer timeframe, I certainly think the pace of progress is picking up.

What do you think are the most promising areas of research to improve care and outcomes for CRC patients, especially stage IV patients?

There are so many areas of promise, but I'll highlight two that I think are really going to be groundbreaking.

First are the tools to identify patients who may have microscopic metastatic disease despite surgery and adjuvant chemotherapy. Using very sensitive circulating tumor DNA (ctDNA) tests, we can now detect, with very high specificity, patients where surgery and adjuvant therapy wasn't enough and microscopic disease remains. For those patients, it's currently a matter of time until the cancer radiographically recurs and reaches the point where it is big enough to be detected with imaging tests. The use of ctDNA is a tremendous opportunity to attack the cancer when there are the smallest number of cancer cells and before a lot of the barriers to immune response from the tumor microenvironment have been established. If we can identify it early enough, there may be opportunities not just to control the cancer, but cure the disease. I think this is going to change how we think about cancer and allow us to accelerate a number of really innovative approaches to improve outcomes.

The second area is the advancement of biomarker technology. When we look back at all the advances that we've made over the years, we could make an argument that a lot of the improvements and outcomes have come from our ability to better identify and characterize the tumors using biomarker technology. We are now at a point where biomarker technology is substantially better than it used to be. For example, we can now identify and do single cell sequencing on tumors. This means that it's not about just taking the totality of the tumor and seeing what mutations are expressed, but we can now look at tens to hundreds of thousands of cells out of a given patient's tumor and understand what's going on in each and every one of those cancer cells. This is an amazing opportunity to understand the heterogeneity of the tumor (differences between the molecular makeup of patients’ tumors).

However, the large amount of data available has substantially challenged our ability to analyze it. Ten years ago when we were doing biomarker research, I could take all the data that was generated and analyze it myself in Excel. Right now, we are getting gigabytes of data from each patient. These data are going to take us into areas that we can't even anticipate yet. Now the challenge (and research bottleneck) is making sense of this information.

Looking forward, what do you see as the most significant barrier to developing new treatment options that work?

First, the ability of CRC to adapt to treatments is daunting. Cancer, in general, can adapt to therapies and develop resistance mechanisms rather frequently. CRC is especially capable of doing this. We've seen in many different studies where a lung cancer patient treated with a drug will develop resistance through one mutation, one pathway. That's ideal because then you can say, ‘Great, let's target that pathway!’ Using the same drug and the same alteration in CRC may lead to a patient that develops 10 different mechanisms of resistance. That is a tremendous challenge because it requires us to figure out how we intercept all 10 of those resistance mechanisms. While that's a challenge, we also recognize this as a potential vulnerability of the cancer cells that we can target.

A second barrier is the limited ability of CRC to even trigger an initial immune response and subsequent limited activity of immunotherapy. This is not due to the fact that there's not enough mutations or not enough neoantigens in CRC. There are plenty, just as many as other tumor types that have responded to immunotherapy, but there are other features that are unique to CRCs, such as the tumor micro-environment and the signaling pathways that limit the effectiveness of immunotherapy.

I think this is where technology is going to be helpful to improve our understanding. However, the number of steps required to get immunotherapy working for CRC is much different than many other solid tumors. When we think about immune responses, there are six or seven major steps required to ultimately get an immune cell to kill a tumor cell. This includes the ability of the cancer cell or the immune system to even acknowledge that there's anything abnormal in the body, and then to generate the correct response to affect cell killing. There are many tumor types that have already gone through several of these steps, but for CRC, we’re often starting at step zero. So we have to train the immune system to go through each one of these steps to get a response to immunotherapy. While this is a barrier, the tools have improved. We're seeing a plethora of approaches, including vaccine approaches, T-cell strategies, and oncolytic viruses, that can help address some of these steps pretty quickly.

What is your advice to patients or advocates looking to help advance CRC research? What can they do? 

The treatment of CRC will continue to advance and we'll make progress. It's really just a question of how fast we can get to where we need to be. Pushing and advocating for research is critical. There are so many ways that that patient advocacy has very positively influenced and helped shape the direction of the field.

I think advocacy is increasingly more effective in being able to exact change at a policy level, a funding level, and in supporting the design of clinical trials.

These efforts are absolutely making a difference at every step of the way. I have no doubt that the acceleration that we're seeing in the field is enabled by this increased advocacy. One such opportunity is patient-to-patient education and awareness activities that can absolutely make a difference in areas such as increasing enrollment in clinical trials and awareness of the need for biomarker testing.

I also think part of the goal should be to enable the next generation of researchers and to support them. These are opportunities where a small amount of support, mentoring, and resources can launch a career focused on CRC research. We can do a better job of supporting the development of new researchers so that they stay committed to research in CRC for their entire careers. That can really pay dividends. As an advocacy community, we can really encourage and direct resources in the right place.

Thank you, Dr. Kopetz for your time! Stay tuned for next month's Scientist Spotlight and be sure to check out the resources linked in this blog to learn more about biomarkers, immunotherapy, and research advocacy.

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